CLINIMIX

Dosage and Administration, Instructions for Use ( 2.3 , 2.7 ) 04/2021 Warnings and Precautions ( 5.5 ) 04/2021 Dosage and Administration ( 2.1 , 2.3 , 2.4 , 2.6 , 2.8 ) 09/2020

1 INDICATIONS AND USAGE CLINIMIX is indicated as a source of calories and protein for patients requiring parenteral nutrition when oral or enteral nutrition is not possible, insufficient, or contraindicated. CLINIMIX may be used to treat negative nitrogen balance in patients. CLINIMIX is indicated as a source of calories and protein for patients requiring parenteral nutrition when oral or enteral nutrition is not possible, insufficient, or contraindicated. CLINIMIX may be used to treat negative nitrogen balance in patients. ( 1 )

2 DOSAGE AND ADMINISTRATION See full prescribing information for information on preparation, administration, instructions for use, dosing considerations, including the recommended dosage in adults and pediatrics, and dosage modifications in patients with kidney disease. ( 2.1 , 2.2 , 2.3 , 2.4 , 2.5 , 2.6 , 2.7 , 2.8 ) 2.1 Preparation Prior to Administration • CLINIMIX is available in a three port container configuration and a two port container configuration. o Three Port Container : the ports consist of one medication port, one additive port and one outlet port. Additives can be introduced to the container through the medication port and lipids through the additive port on the three port container. o Two Port Container : the ports consist of one medication port and one outlet port. Additives, including lipids, can be introduced to the container through the medication port on the two port container. • Tear protective overwrap at slit and remove solution container. Small amounts of moisture may be found on the solution container from water permeating from inside the container. The amount of permeated water is insufficient to affect the solution significantly. If larger amounts of water are found, the container should be checked for tears or leaks. • Inspect the container prior to activation. Some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. Evaluate the following: o If the outlet or additive port protectors are damaged, detached, or not present, discard container as solution path sterility may be impaired. o Check to ensure seal between chambers is intact, solutions are contained in separate chambers, and the content of the individual chambers is clear, colorless or slightly yellow. Discard if the seal is broken or if the solution is bright yellow or yellowish brown. o Check for minute leaks by separately squeezing each chamber. If external leaks or leakage between the chambers are found, discard solution as sterility or stability may be impaired. • Lipids and/or additives can be introduced to the container after opening seal between chambers. Because additives may be incompatible, evaluate all additions to the plastic container for compatibility. Activate chambers of container prior to introduction of additives. Mix thoroughly when additives have been introduced. Supplemental medication may be added with a 19 to 22 gauge needle through the medication port. • Calcium and phosphate ratios must be considered. Excess addition of calcium and phosphate, especially in the form of mineral salts, may result in the formation of calcium phosphate precipitates [see Warnings and Precautions (5.1) ] . • Inspect the container to ensure precipitates have not formed during the mixing or addition of additives. A slight yellow color does not alter the quality and efficacy of this product. If lipid has been added, ensure the emulsion has not separated. Separation of the emulsion can be visibly identified by a yellowish streaking or the accumulation of yellowish droplets in the mixed emulsion. Discard the admixture if any of the above are observed. 2.2 Important Administration Instructions • Set the vent to the closed position on a vented intravenous administration set to prevent air embolism. • Use a dedicated line without any connections to avoid air embolism. • CLINIMIX is for intravenous infusion only into a central or peripheral vein. The choice of a central or peripheral venous route should depend on the osmolarity of the final infusate. Solutions with osmolarity of 900 mOsm/L or greater must be infused through a central catheter [see Warnings and Precautions (5.6) ] . o For central vein infusion only: CLINIMIX 4.25/10, 5/15, 5/20, 8/10, 8/14 o For central or peripheral vein infusion: CLINIMIX 4.25/5, 6/5 • The solution should be inspected for precipitates before admixing, after admix …

3 DOSAGE FORMS AND STRENGTHS CLINIMIX injection is available in 1000 mL and 2000 mL dual chamber containers. The individual chambers contain essential and nonessential amino acids and dextrose. Table 7 describes the individual components of CLINIMIX. Table 7: INGREDIENTS PER 100mL OF CLINIMIX Strength of CLINIMIX CLINIMIX 4.25/5 sulfite‐free (4.25% Amino Acid in 5% Dextrose) Injection CLINIMIX4.25/10 sulfite‐free (4.25% Amino Acid in 10% Dextrose) Injection CLINIMIX 5/15 sulfite‐free (5% Amino Acid in 15% Dextrose) Injection CLINIMIX 5/20 sulfite‐free (5% Amino Acid in 20% Dextrose) Injection CLINIMIX 6/5 sulfite‐free (6% Amino Acid in 5% Dextrose) Injection CLINIMIX 8/10 sulfite‐free (8% Amino Acid in 10% Dextrose) Injection CLINIMIX 8/14 sulfite‐free (8% Amino Acid in 14% Dextrose) Injection Dextrose Hydrous, USP (g/100 mL) 5 10 15 20 5 10 14 Amino Acids (g/100 mL) 4.25 4.25 5 5 6 8 8 Total Nitrogen (mg/100 mL) 702 702 826 826 990 1320 1320 Essential Amino Acids (mg/100 mL) Leucine 311 311 365 365 438 584 584 Isoleucine 255 255 300 300 360 480 480 Valine 247 247 290 290 348 464 464 Lysine (added as the hydrochloride salt) 247 247 290 290 348 464 464 Phenylalanine 238 238 280 280 336 448 448 Histidine 204 204 240 240 288 384 384 Threonine 179 179 210 210 252 336 336 Methionine 170 170 200 200 240 320 320 Tryptophan 77 77 90 90 108 144 144 Nonessential Amino Acids (mg/100 mL) Alanine 880 880 1035 1035 1242 1656 1656 Arginine 489 489 575 575 690 920 920 Glycine 438 438 515 515 618 824 824 Proline 289 289 340 340 408 544 544 Serine 213 213 250 250 300 400 400 Tyrosine 17 17 20 20 24 32 32 Anion Profile (mEq/L) Balanced by ions from amino acids. Acetate Derived from glacial acetic acid (for pH adjustment). 37 37 42 42 53 71 71 Chloride Contributed by lysine hydrochloride and hydrochloric acid (for pH adjustment). 17 17 20 20 24 32 32 pH pH of sulfite-free amino acid injection in the outlet port chamber may be adjusted with glacial acetic acid and pH of dextrose injection port chamber may be adjusted with hydrochloric acid. (Range) 6.0 (4.5 to 7.0) 6.0 (4.5 to 7.0) 6.0 (4.5 to 7.0) 6.0 (4.5 to 7.0) 6.0 (4.5 to 7.0) 6.0 (4.5 to 7.0) 6.0 (4.5 to 7.0) Osmolarity (mOsmol/L) (calc) 675 930 1255 1505 850 1308 1520 Caloric Content (kcal/L) From Dextrose 170 340 510 680 170 343 477 From Amino Acids 170 170 200 200 240 320 320 TOTAL (Dextrose and Amino Acids) 340 510 710 880 410 663 797 CLINIMIX injection is available in multiple strengths. See full prescribing information for detailed description of each formulation. ( 3 , 11 )

4 CONTRAINDICATIONS The use of CLINIMIX is contraindicated in: • Patients with known hypersensitivity to one or more amino acids or dextrose [see Warnings and Precautions (5.2) ] . • Patients with inborn errors of amino acid metabolism due to risk of severe metabolic and neurologic complications. • Patients with pulmonary edema or acidosis due to low cardiac output. • Known hypersensitivity to one or more amino acids or dextrose. ( 4) • Inborn errors of amino acid metabolism. ( 4 ) • Patients with pulmonary edema or acidosis due to low cardiac output. ( 4 )

6 ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in other sections of the prescribing information. • Pulmonary embolism due to pulmonary vascular precipitates [see Warnings and Precautions (5.1) ] • Hypersensitivity reactions [see Warnings and Precautions (5.2) ] • Risk of Infections [see Warnings and Precautions (5.3) ] • Refeeding syndrome [see Warnings and Precautions (5.4) ] • Hyperglycemia or hyperosmolar hyperglycemic state [see Warnings and Precautions (5.5) ] • Vein damage and thrombosis [see Warnings and Precautions (5.6) ] • Hepatobiliary disorders [see Warnings and Precautions (5.7) ] • Parenteral Nutrition Associated Liver Disease [see Warnings and Precautions (5.9) ] • Electrolyte imbalance and fluid overload [see Warnings and Precautions (5.10) ] The following adverse reactions from voluntary reports or clinical studies have been reported with CLINIMIX. Because many of these reactions were reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. • Diuresis • Extravasation • Glycosuria • Hyperglycemia • Hyperosmolar coma Adverse reactions include diuresis, extravasation, glycosuria, hyperglycemia, and hyperosmolar coma. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Baxter Healthcare Corporation at 1-866-888-2472 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch

8 USE IN SPECIFIC POPULATIONS Pediatric Use : increased risk of hypoglycemia/hyperglycemia: monitor serum glucose concentrations. ( 8.4 ) 8.1 Pregnancy Risk Summary There are no adequate or well-controlled studies in pregnant women with CLINIMIX. Additionally, animal reproduction studies have not been conducted with amino acids and electrolytes and dextrose. It is not known whether CLINIMIX can cause fetal harm when administered to a pregnant woman. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. However, the estimated background risk in the U.S. general population of major birth defects is 2 to 4% and of miscarriage is 15 to 20% of clinically recognized pregnancies. Clinical Considerations Disease-Associated Maternal and/or Embryo-Fetal Risk Based on clinical practice guidelines, parenteral nutrition should be considered in cases of severe maternal malnutrition where nutritional requirements cannot be fulfilled by the enteral route because of the risks to the fetus associated with severe malnutrition, such as preterm delivery, low birth weight, intrauterine growth restriction, congenital malformations and perinatal mortality. 8.2 Lactation Risk Summary It is not known whether CLINIMIX is present in human milk. There are no data on the effects of CLINIMIX on the breastfed infant or on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for CLINIMIX and any potential adverse effects on the breastfed child from CLINIMIX or from the underlying maternal condition. 8.4 Pediatric Use Safety and effectiveness of CLINIMIX in pediatric patients have not been established by adequate and well-controlled studies. Use of dextrose, amino acid infusions and electrolytes in pediatric patients is based on clinical practice [see Dosage and Administration (2.8) ] . Newborns, especially those born premature and with low birth weight, are at increased risk of developing hypo – or hyperglycemia and therefore need close monitoring during treatment with intravenous glucose solutions to ensure adequate glycemic control in order to avoid potential long term adverse effects. Hypoglycemia in the newborn can cause prolonged seizures, coma and brain damage. Hyperglycemia has been associated with intraventricular hemorrhage, late onset bacterial and fungal infection, retinopathy of prematurity, necrotizing enterocolitis, bronchopulmonary dysplasia, prolonged length of hospital stay, and death. Plasma electrolyte concentrations should be closely monitored in the pediatric population as this population may have impaired ability to regulate fluids and electrolytes. Because of immature renal function, preterm infants receiving prolonged treatment with CLINIMIX may be at risk of aluminum toxicity [see Warnings and Precautions (5.8) ] . Patients, including pediatric patients, may be at risk for Parenteral Nutrition Associated Liver Disease (PNALD) [see Warnings and Precautions (5.9) ] . Hyperammonemia is of special significance in infants (birth to two years). This reaction appears to be related to a deficiency of the urea cycle amino acids of genetic or product origin. It is essential that blood ammonia be measured frequently in infants [ see Warnings and Precautions (5.7) ] . 8.5 Geriatric Use Clinical studies of CLINIMIX did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from other younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or drug therapy.

12.1 Mechanism of Action CLINIMIX is used as a supplement of nutrition in patients, providing macronutrients (amino acids and dextrose) parenterally. The amino acids provide the structural units that make up proteins and are used to synthesize proteins and other biomolecules or are oxidized to urea and carbon dioxide as a source of energy. The administered dextrose is oxidized to carbon dioxide and water, yielding energy.

11 DESCRIPTION CLINIMIX sulfite-free (amino acids in dextrose) injection for intravenous use consists of sterile, nonpyrogenic, hypertonic solutions in a dual chamber container. The outlet port chamber contains essential and nonessential amino acids. The formulas for the individual amino acids found in CLINIMIX sulfite-free (amino acids in dextrose) injections are provided in Table 8 . Table 8: Formulas for Amino Acids Essential Amino Acids Leucine (CH 3 ) 2 CHCH 2 CH (NH 2 ) COOH Isoleucine CH 3 CH 2 CH (CH 3 ) CH (NH 2 ) COOH Valine (CH 3 ) 2 CHCH (NH 2 ) COOH Lysine (added as the hydrochloride salt) H 2 N (CH 2 ) 4 CH (NH 2 ) COOH Phenylalanine (C 6 H 5 ) CH 2 CH (NH 2 ) COOH Histidine (C 3 H 3 N 2 ) CH 2 CH (NH 2 ) COOH Threonine CH 3 CH (OH) CH (NH 2 ) COO Methionine CH 3 S (CH 2 )2 CH (NH 2 ) COOH Tryptophan (C 8 H 6 N) CH 2 CH (NH 2 ) COOH Nonessential Amino Acids Alanine CH 3 CH (NH 2 ) COOH Arginine H 2 NC (NH) NH (CH 2 )3 CH (NH 2 ) COOH Glycine H 2 NCH 2 COOH Proline [(CH 2 ) 3 NH CH] COOH Serine HOCH 2 CH (NH 2 ) COOH Tyrosine [C 6 H 4 (OH)] CH 2 CH (NH 2 ) COOH The injection port chamber contains dextrose. Dextrose, USP, is chemically designated D-glucose, monohydrate (C 6 H 12 O 6 • H 2 O) and has the following structure: Dextrose is derived from corn. See Table 7 for composition, pH, osmolarity, ionic concentration and caloric content of the admixed product [ see Dosage Forms and Strengths (3)]. The dual chamber container is a lipid-compatible plastic container (PL 2401 Plastic). CLINIMIX contains no more than 25 mcg/L of aluminum. Structural Formula Dexrose Hydrous, USP

10 OVERDOSAGE An increased infusion rate of CLINIMIX cause hyperglycemia, hyperosmolality, and adverse effects on water and electrolyte balance [see Warnings and Precautions (5.5 , 5.10) ]. Severe hyperglycemia and severe dilutional hyponatremia, and their complications, can be fatal. Discontinue infusion and institute appropriate corrective measures in the event of overhydration or solute overload during therapy, with particular attention to respiratory and cardiovascular systems . For current information on the management of poisoning or overdosage, contact the National Poison Control Center at 1-800-222-1222 or www.poison.org .

16 HOW SUPPLIED/STORAGE AND HANDLING CLINIMIX (amino acids in dextrose) injection (sulfite-free) is available in 1000 mL and 2000 mL volumes (See Table 9 ). Table 9: CLINIMIX Formulations (per 07-19-00-3604 and BE-30-03-648) After mixing, the product represents 1000 mL Code and NDC Number 2000 mL Code and NDC Number CLINIMIX 4.25/5 sulfite‐free (4.25% Amino Acid in 5% Dextrose) Injection Code 2B7726 NDC 0338‐1133‐03 Code 2B7704 NDC 0338‐1089‐04 CLINIMIX 4.25/10 sulfite‐free (4.25% Amino Acid in 10% Dextrose) Injection Code 2B7727 NDC 0338‐1134‐03 Code 2B7705 NDC 0338‐1091‐04 CLINIMIX 5/15 sulfite‐free (5% Amino Acid in 15% Dextrose) Injection Code 2B7730 NDC 0338‐1137‐03 Code 2B7709 NDC 0338‐1099‐04 CLINIMIX 5/20 sulfite‐free (5% Amino Acid in 20% Dextrose) Injection Code 2B7731 NDC 0338‐1138‐03 Code 2B7710 NDC 0338‐1101‐04 CLINIMIX 6/5 sulfite‐free (6% Amino Acid in 5% Dextrose) Injection Code EADB9913 NDC 0338‐0198-06 _____ CLINIMIX 8/10 sulfite‐free (8% Amino Acid in 10% Dextrose) Injection Code EADB9933 NDC 0338‐0188-06 Code EADB9935 NDC 0338‐0194-04 CLINIMIX 8/14 sulfite‐free (8% Amino Acid in 14% Dextrose) Injection Code EADB9953 NDC 0338‐0180-06 Code EADB9955 NDC 0338‐0184-04 Table 9: CLINIMIX Formulations (per BE-30-04-047) After mixing, the product represents 1000 mL Code and NDC Number 2000 mL Code and NDC Number CLINIMIX 4.25/5 sulfite‐free (4.25% Amino Acid in 5% Dextrose) Injection Code 2B7726L NDC 0338‐7001-01 Code 2B7704L NDC 0338‐7003-01 CLINIMIX 4.25/10 sulfite‐free (4.25% Amino Acid in 10% Dextrose) Injection Code 2B7727L NDC 0338‐7005-01 Code 2B7705L NDC 0338‐7007-01 CLINIMIX 5/15 sulfite‐free (5% Amino Acid in 15% Dextrose) Injection Code 2B7730L NDC 0338‐7009-01 Code 2B7709L NDC 0338‐7011-01 CLINIMIX 5/20 sulfite‐free (5% Amino Acid in 20% Dextrose) Injection Code 2B7731L NDC 0338‐7013-01 Code 2B7710L NDC 0338‐7015-01 CLINIMIX 6/5 sulfite‐free (6% Amino Acid in 5% Dextrose) Injection Code EADB9913 NDC 0338‐0198-06 _____ CLINIMIX 8/10 sulfite‐free (8% Amino Acid in 10% Dextrose) Injection Code EADB9933 NDC 0338‐0188-06 Code EADB9935 NDC 0338‐0194-04 CLINIMIX 8/14 sulfite‐free (8% Amino Acid in 14% Dextrose) Injection Code EADB9953 NDC 0338‐0180-06 Code EADB9955 NDC 0338‐0184-04 Minimize exposure of CLINIMIX to heat and avoid excessive heat. Protect from freezing. Store CLINIMIX at room temperature (25°C/77°F) (may briefly store at up to 40°C/104°F). Refrigerated storage is limited to 9 days once the protective overwrap has been opened. Do not use if the protective overwrap has been previously opened or damaged. For storage of admixed solutions see Dosage and Administration (2.3 , 2.4 ) .